Powder flow is critical during formulation of powders, granules & during tableting as powders must flow easily and uniformly to ensure weight uniformity and production with consistent and reproducible properties. In order for powder to flow effectively, lubricants are essential because they reduce cohesiveness of the powder by reducing inter-particle friction and help the powder to flow without affecting dose uniformity, avoid picking, sticking, improper filling, clogging of equipment, improper emptying from sachets, capsules etc (Physical Pharmacy, Fourth Edition, Alfred Martin, Lippincott, Williams and Wilkins Philadelphia; 2001; Page 447-448). The most commonly used lubricants and flow aids are magnesium stearate, stearic acid salts and derivatives, talc & colloidal silicon dioxide. Lubricants, flow aids, glidants, anti-adherents are used interchangeably and have more or less the same purpose.
U.S. Pat. No. 7,381,428 describes a stabilized composition of lanthanum carbonate having 13.4-13.9% to 32.2-33.3% by weight of the composition as elemental lanthanum and excipients like stabilizing agent (dextrates), lubricants & glidants (like magnesium stearate, talc, polyethylene glycol, silica, colloidal silicon dioxide, hydrogenated vegetable oil, glyceryl behenate or glyceryl monostearate). Specification discloses lanthanum carbonate degrades to lanthanum hydroxycarbonate and the process is accelerated in presence of moisture/water and heat.
U.S. Pat. No. 7,465,465 describes lanthanum carbonate chewable tablets and powder formulations and states that lanthanum compounds such as lanthanum carbonate have poor flow characteristics and it represents a challenge while formulating compositions having a high drug load. The powder formulations contain the active along with pharmaceutically acceptable excipients which specifically include flow agents like silica, colloidal anhydrous silica, magnesium stearate, talc, polyethylene glycol, hydrogenated vegetable oils, glyceryl behenate & glyceryl monostearate. The flow agent is used in amounts from about 0.1% to about 5.0%. The patent advises against the method of wet granulation and drying as it may affect the hydration state of Lanthanum carbonate, an important aspect related to its biological properties. U.S. Pat. No. 8,263,119 describes a capsule encapsulating a powder composition of lanthanum carbonate and a lubricant such as talc and/or colloidal silicon dioxide. Dextrates is used as a diluent, colloidal silicon dioxide as flow aid and magnesium stearate as a lubricant. U.S. Pat. No. 8,697,132 & U.S. Pat. No. 8,980,327 describe an oral pharmaceutical powder containing lanthanum carbonate, dextrates, crospovidone, colloidal silicon dioxide and talc and states that the powder composition has similar plasma lanthanum carbonate concentration as that of a chewable tablet comprising lanthanum carbonate, dextrates, colloidal silicon dioxide and magnesium stearate. The formulation was optimized using various ingredients. It further states that lubricants prevent the formulation from sticking to the process equipment while flow aids help the formulation to flow freely during and after being processed. The lubricant amount can be from about 0.01% to about 0.05%, preferably from about 0.01% to about 0.04%, and most desirably from about 0.01% to about 0.03% by weight of the powder or the capsule contents of the formulation. The flow aid amount can be from about 0.1% to about 4%, preferably from about 0.1% to about 3%, and most desirably from about 0.1% to about 2% by weight of the powder or the capsule contents of the formulation. Examples state that lubricants when added lead to better flow properties. The patent lays emphasis on the fact that flow aids, lubricants and other excipients need to be thoroughly studied and optimized as they affect the dissolution of the final dosage form. Example 15 in the specification demonstrates the manufacture of unit dose by using a dosing auger of 8 mm and 60-70% of auger speed. U.S. Pat. No. 8,974,824 describes a wet granulated composition of lanthanum carbonate octahydrate devoid of monosaccharides and disaccharides. The specification discloses lubricants like calcium stearate, magnesium stearate, sodium lauryl sulfate, talc, mineral oil, stearic acid, zinc stearate, colloidal silicon dioxide, glyceryl behenate, polyethylene glycol, sodium stearyl fumarate, hydrogenated cottonseed oil, sodium benzoate, leucine or combinations thereof. US 2014/0178467 & US 2015/0030695 claim oral lanthanum carbonate compositions comprising specific excipients like dextrates, colloidal silicon dioxide, flow aids and lubricants. Impact of various ingredients (emphasis on lubricants and flow aids here) on the dissolution profile of the formulations were studied. The formulations were stored at 60° C. for a week. Specification indicates that extensive optimization studies were conducted for selecting lubricants and flow aids. Specification also mentions that lubricants stop the formulation from sticking to the process equipment while flow aids enable the formulations to flow freely while being processed, and colloidal silicon dioxides acts as a flow aid as well as lubricant.
U.S. Pat. No. 7,179,486 describes tablet compositions prepared by granulation. The patent emphasizes the importance of good flow properties to avoid improper filling of die cavities and entrapment and describes lubricants as typical ingredients of granules.
The prior art indicates that flow aids and lubricants are essential part of powder compositions especially for a compound having very poor flow properties like lanthanum carbonate. It lays special emphasis on these excipients for maintaining the ease of processing and overall quality of the product.
Flow aids and lubricants need to be thoroughly studied and their quantity needs to be optimized as they affect the dissolution of the final dosage form. Moreover a large number of excipients add to the bulk, preformulation study steps, processing steps and overall cost of the product. Thus, the more the excipients required, more is the cost as well as the manufacturing steps. Moreover, powders & granules require mechanical devices like auger for conveying them during filling operation & the process parameters of the conveyor auger like dimension and speed need to be optimized while filling into suitable containers. There is a need in the art to develop a better formulation of lanthanum carbonate which is cost effective and more precisely, uses limited number of excipients without compromising on the quality of the formulation.
There is a need in the art to develop formulations which provide powders & granules with desirable characteristics for formulation process and packaging and yet contain no lubricants or flow aids.
Lanthanum carbonate has a tendency to degrade to lanthanum hydroxycarbonate. The degradation process is accelerated by moisture and heat. The regulatory requirements preclude detectable decarboxylation for administration to patients. Thus there is a need in the art to develop lanthanum carbonate powder compositions that are stable against substantial decarboxylation to lanthanum hydroxycarbonate. We have surprisingly found that lanthanum carbonate compositions can be formulated without lubricants and/or flow aids. These formulations have flow properties comparable with that of compositions which contain flow aids and lubricants. It is a finding of the present invention that lanthanum carbonate compositions can be formulated using dextrates alone as excipient without the use of other additional excipients as necessitated by the prior art.
The present invention helps to reduce cost & save time as it reduces the time required for optimization of excipients like lubricants, flow aids or binders and reduces powder bulk.